Azauridine derivatives



United States Patent ABSTRACT OF THE DISCLOSURE This-invention relatesto the new chemical compounds, the3rsubstituted-Z-ribofuranosyl-as-triazin-S (2H) ones (i.e.,3-substituted azauridines),-which are useful as disinfectants and asantibacterial agents. The compounds are prepared by treating a.3-substituted-mercapto-Z-tri-O- benzoylribofuranosyl-as-triazin-5(2H)-one with ammonia or halogen to yield the corresponding3-substituted final products. Alternatively, the final products can beformed by treating a 3-substituted-thio-as-triazin-5(2H)-one with anamine, ammonia or halogen to yield theS-Substitutedas-triazin-5(2H)-one, then with a mercuric salt to yieldthe corresponding 2-mercuri derivative, then with tri-O-benzoyl-D-ribofuranosyl chloride to yield the corresponding2tri-O-benzoylribofuranosyl. drivative, and finally with a strongbase toyield the final product.

This application is a continuation-in-part of my application, Ser. No.247,816, filed Dec. 28, 1962, now abandoned.

This invention relates to the synthesis of new heterocyclic organiccompounds. More particularly, this invention relatesto the synthesis ofnew 3-substituted Z-ribofuranosyl-as-triazin-S(2H)-ones (i.e.,B-substituted azauridines) which may be represented by the followingformula (ribofuranosyD-N wherein Z may represent halogen (e.g., chloroor bromo), amino, furfurylamino, morpholino or piperidino.

It is an object of this invention to prepare new 3-substitutedazauridine derivatives and more particularly to prepare thesederivatives by a new and improved method, which entails the preparationof new intermediates and leads to the production of the desiredproducts.

The new azauridine derivatives and the intermediates therefor(particularly the mercuri intermediates) in aqueous solution orsuspension possess antibacterial activity and can be used asdisinfectants. For this purpose they are dissolved or suspended inwater, preferably also containing a detergent, at a concentration ofabout 0.5% to about 5% and may be used as washes todisinfect walls andfloors.

The objects of this invention may be accomplished by various methods.The general and preferred method involves the employment of a compoundof the Formula I wherein R is a hydrocarbon radical of less than twelvecarbon atoms, such as alkyl, preferably lower alkyl (e.g., methyl,ethyl, propyl, butyl, amy-l, and hexyl); aralkyl, preferably monocyclicaryl lower alkyl (e.g., benzyl, phenethyl, fl-phenylpropyl, and o, m orp-tolylethyl); alkenyl, preferably lower alkenyl (e.g., allyl);aralkenyl, preferably monocyclic aryl lower alkenyl (e. g., cinnamyl)and cycloalkyl (e.g., cyclopropyl and cyclohexyl), as a startingmaterial.

The starting material of Formula I may be prepared in accordance withthe procedures set forth in my application, Ser. No. 39,768, filed June30, 1960, and now US. Patent No. 3,135,737.

The desired products of this invention may be obtained by treating thestarting material of Formula I with an ammonia gas or halogen gas in acold, methanol solution. It has been surprisingly found by thisprocedure that the 3-R-S radical is removed from the thiazinyl nucleusand replaced by the respectivereagent employed, i.e., NH or halogen,while debenzoylation simultaneously takes place at the 2-position toyield the desired new 3-substituted-2-ribofuranosyl-as-triazin-5(2I-I)-ones, i.e., 3-amino or 3-halo-azauridines.

In an alternative method which may be employed in the production of thenew compounds of this invention, a tautomeric compound of the Formula IIwherein R is as hereinbefore defined, may first be treated to replacethe 3-R-S radical, as by reaction with morpholine, piperidine,furfurylamine, ammonia, or a halogen (e.g., chlorine or bromine) toyield the respective 3-substituted intermediates, which are also newcompounds of this invention.

The starting material of Formula II may also be prepared in accordancewith the procedures set forth in said U.S. Patent No. 3,135,737.

The new 3-substituted intermediates may then be reacted with a mercuricsalt, preferably derived from an acid such as the hydrohalic acids(e.g., hydrochloric and hydrobromic acids), nitric acid, sulfuric acidand organic acids, such as the lower alkanoic acids (e.g., acetic,propicnic and butyric acids) and aromatic acids (e.g., benzoic and o, mand p-toluic acids) to form a new compound of the Formula III wherein Zis halogen, amino, furfurylamino, morpholino or piperidino, X is theanion of the mercuric acid salt and n is the integer one or two.

The reaction is preferably conducted in an inert solvent medium, such asthe lower alkanols (e.-g., methanol and ethanol) and dimethylformamide.Reaction speed may be increased by warming the solution of the tworeactants, but reaction will occur at room temperature. The ratio ofreactants will determine the nature of the reaction product to theextent that if two moles of the triazine are employed for each mole ofthe mercuric salt, the reaction product will contain two moles of thetriazinyl moiety compound of Formula III wherein n is equal to 2)whereas if a one to One ratio is employed, the reaction product will bea mercuric acid salt of Formula III wherein n is equal to one.

A compound of Formula III is next reacted with a tri-O-benzoyl-D-ribofuranosyl chloride to yield a new compound of the FormulaIV:

N (tri-O-bcnzoyh'ibOIuranosyD-N wherein Z is as hereinbefore defined.The reaction is conducted in a solvent medium and preferably underreflux conditions. Suitable solvents are non-polar solvents such as thearomatic hydrocarbons (e.g., benzene and toluene). The reaction productis isolated from the liquid port on of the reaction mixture byfiltration and concentration of the filtrate.

Compounds of the Formula IV may then be converted to the desired3-substituted azauridines of this invention by hydrolysis with a strongbase, such as anhydrous ammonia or sodium methoxide, which hydrolysisresults in debenzoylation at the 2-position to yield the desiredproducts.

The following examples are presented to more fully illustrate theinvention, all temperatures being expressed in degrees centigrade.

Example l.3 amino-Z-ribofuranosyl-as-triazin-S-(2H)- one A solution ofabout 5 g. of amorphous and impure 3-methylthio-2-(tri-O-benzoylribofuranosyl)-as-triazin 5- (2H)-one in 250ml. of methanol is saturated at -5 with NH gas. The batch is allowed toreach room tempenature where it is held for 4 days. Concentration of themixture to a volume of 100 ml., followed by filtration leads to 550 mg.of crude 3-amino-Z-ribofuranosyl-as-triazin--(2H)-one. Purification isaccomplished by dissolving the crude material in 12 ml. of HCl,decolorization of the solution with activated charcoal and finallyneutralization to pH 8.4 with 28% aqueous NH The crystals weigh 425 mg.,M.P. 243245 decomp. (with pre-darkening) Analysis.Calcd for C H N O C,39.34; H; 4.95; N, 22.94. Found: C, 39.46; H, 5.04; N, 23.05.

Example 2.-3-chloro-2-ribofuranosyl-astriazin-5 (2H) -one Following theprocedure set forth in Example 1 but substituting an equivalent amountof chlorine gas for ammonia gas yields3-chloro-2-ribofuranosyl-as-triazin- 5 (2H)-one.

Similarly, following the procedure set forth in Example 1 butsubstituting an equivalent amount of bromine gas for ammonia gas thereis obtained 3-bromo-2-ribofuranosyl-as-triazin-S (2H)-one.

Example 3.--3-(furfurylamino)-as-triazin-5 (4H)-one Example 4.3-(piperidino -as-triazin-5 (4H) -one Following the procedure set forth inExample 3 but substituting an equivalent amount of piperidine forfurfurylamine yields 3- (piperidino)-as-triazin-5 (4H)-one.

Similarly, following the procedure set forth in Example 3 butsubstituting an equivalent amount of morpholine for furfurylamine yields3-(morpholino)-as-triazin 5(4H)- one.

Example 5 .-3-chloro-as-triazin-5 (4H) -one Following the procedure setforth in Example 3 but substituting an equivalent amount of chlorine forfurfurylamine there is obtained 3-chloro-as-tr1az1n-5(4H)- one. q

Similarly, following the procedure of Example 3 but substituting anequivalent amount of bromine for furfurylamine yields3-bromo-as-triaZin-5(4H)-one.

Example 6.3-amino-as-triazin-5 (4H)-one A total of 7.72 g. of3-(methylthio)-as-triazin-S(4H)- one dissolved in 216 ml. of 28% aqueousammonia is heated in sealed tubes at 125 for approximately 20 hours.After cooling and opening the tubes the solution is concentrated to asmall volume and filtered. The material is dissolved in ml. of 5%hydrochloric acid and polish filtered. The filtrate is neutralized to pH7.2, causing precipitation of 3.1 g. of product, M.P. 300 (some decreasefrom about 265). A further 1.1 g. of product is obtained by neutralizingthe original mother liquor.

Analysis.0alcd for C H N O: C, 32.14; H, 3.60; N, 49.99. Found: C,32.95; H, 3.82; N, 50.30.

Example 7.2-mercuri-3-amino-as-triazin-5 (2H) -one To a hot solution of1.12 g. of 3-amino-as-triazin-5 (4H)-one in 60 ml. of hotdimethylformamide is added to a warm solution of 1.6 g. of mercuricacetate in 10 ml. of hot methanol. After cooling the'precipitate isfiltered and washed successively with water, ethanol and ether giving1.4 g. of 2-mercuri-3-amino-as-triazin-5(2H)-one.

Similarly, following the procedure set forth in Example 7 butsubstituting an equivalent amount of 3-(furfurylamino)-as-triazin 5 (2H)one for 3-amino-as-triazin-5 (4H)-one yields 2-mercuri-3(furfurylamino}as-triazin- 5(2H)-one.

Similarly, following the procedure set forth in Example 7, butsubstituting equivalent amounts of 3(morpholino)- as-triazin 5(4H)-one,3-(piperidino)-as-triazin-5(4H)- one, 3-(chloro)-as-triazin-5(4H)-oneand 3-(bromo)-astriazin-5(4H)-one, for 3-amino-as-tn'azin 5(4H) one,yields respectively 2-rnercuri-3-(morpholino)-as-triazin- 5(2H)-one,2-mercuri-3-(piperidino)-as-triazin 5(2H) one and2-mercuri-3-(bromo)-as-triazin-5-(2H)-one.

Example 8.-3-amino-2-(tri-O-benzoylribofuranosyl)-astriazine-S 2H) -oneTo a dry suspension of 1.35 g. of 2-mercuri-3-aminoas-triazin-5(2H)-onein 100 ml. of toluene is added 7.0 g. of tri-O-benzoyl-D-ribofuranosylchloride in 50 ml. of benzene. The mixture is distilled to remove thebenzene and then refluxed for 45 minutes. On cooling, the mixture isfiltered and the filtrate is concentrated to dryness and the residuepicked up in chloroform. The extract is washed with dilute KI solutionand water. After drying, the extract is concentrated to leave as residue3-amino-2- (tri-O-benzylribofuranosyl) -as-triazin-5 (2H) -one.

Similarly, following the procedure of Example 8 but substitutingequivalent amounts of 2-mercuri-3 furfurylamino -as-triazin-5 2H) -one;

2-mercuri-3- (pipcridino -as-triazin-5 (2H) -one;

2-mercuri-3 (morpholino) -as-triazin-5 2H) -one and 2-mercuri-3-( chloro-as-triazin-5 2H) -one for 2-mercuri-3- amino) -as-triazin-5 (2H) -oneyields 3- (furfurylamino -2 (tri-O-benzoylribofuranosyl) -astriazin-S2H) -one;

3-(piperidino -2 (tri-O-benzoylribofuranosyl) -as-triazin- 5 (2H)one;

3-(morpholino -2- (tri-O-benzoylribofuranosyl) -as-triazin-S (2H) -oneand 3-(chloro) -2- (tri-O-benzoylribofuranosyl) -as-triazin- 5 (2H)-one, respectively.

Example 9.-3-amino-2-ribofuranosyl-as-triazin- 5 (2H) -one A solution of3-amino-2-(tri-O-benzoylribofuranosyl)- 3 -(furfurylarnino -2-(tri-O-benzoylribofuranosyl -astriazin-5 (2H -one,

3-(piperidino -2- (tri-O-benzoylribofuranosyl) -as-triazin- 5 (2H -one;

3-(morpho1ino) -2- (tri-O-benzoylribofuranosyl) -as-tria- Zin-S 2H -oneand 3-chloro-2- (tri-O-benzylribofuranosyl -as-triazin- 5 2H -one for3-amino-2- tri-O-henzoylribofuranosyl -as-triazin- 5 2H) -one yields3-(furfurylamino -2-ribofuranosyl-as-triazin-S 2H) -one (3-furfurylaminoazauridine);

3- (piperidino -2-ribofuranosyl-as-triazin-S (2H -one (3- piperidinoazauridine);

3 (morpholino) -2-ribofuranosyl-as-triazin-S- 2H) -one (3-morpholinoazauridine); and

3 -chloro-2-ribofuranosyl-as-triazin-5 (2H -one azauridine (3-chloroThis invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound of the formula (X) 2-n-Hg wherein Z is selected from thegroup consisting of halogen, amino, furfurylamino, morpholino andpiperidino; X is an anion; and n is a positive integer less than 3.

2. The compound of claim 1 having the name 2-mercuri- 3-amino-as-triazin-5 2H -one.

3. A compound of the formula Z-C =0 N wherein Z is selected from thegroup consisting of halogen, amino, furfrylamino, morpholino andpiperidino.

4. The compound of claim 3 having the name3-(furfurylamino)-2-(tri-O-benoylribofuranosyl)-as-triazin 5- (2H)-one.

5. The compound of claim 3 having the name 3-amino- 2 (tri Obenzoylribofuranosyl) as triazin 5(2H)- one.

6. A compound of the formula (ribofuranosyD-N wherein Z is selected fromthe group consisting of halogen, amino, furfurylamino, morpholino andpiperidino.

7. The compound of claim 6 having the name 3-amin0-2-ribofuranosyl-as-triazin-S 2H) -one.

8. The compound of claim 6 having the name 3-chloro-2-ribofuranosyl-as-triazin-5 2H) -one.

9. The compound of claim 6 having the name 3-(furfurylamino-2-ribofuranosyl-as-triazin-S (2H) -one.

10. 3-(furfurylamino)-as-triazin-5(2H)-one.

References Cited UNITED STATES PATENTS 3,135,737 6/1964 Restivo 260211.5

FOREIGN PATENTS 755,036 8/ 1956 Great Britain.

LEWIS GOTTS, Primary Examiner.

I. R. BROWN, Assistant Examiner.

